Boosting synergism of chemo- and immuno-therapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules.
10.1016/j.apsb.2023.08.029
- Author:
Ge SONG
1
;
Minghui LI
1
;
Shumin FAN
1
;
Mengmeng QIN
1
;
Bin SHAO
2
;
Wenbing DAI
1
;
Hua ZHANG
1
;
Xueqing WANG
1
;
Bing HE
1
;
Qiang ZHANG
1
Author Information
1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
2. Department of Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing 100142, China.
- Publication Type:Journal Article
- Keywords:
Bisphosphonate coordination lipid nanogranules;
Ferroptosis;
Mevalonate metabolism;
Mitochondrial metabolism;
Nano-systematic biology
- From:
Acta Pharmaceutica Sinica B
2024;14(2):836-853
- CountryChina
- Language:English
-
Abstract:
Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.
